A critical epithelial survival axis regulated by MCL-1 maintains thymic function in mice

Blood. 2017 Dec 7;130(23):2504-2515. doi: 10.1182/blood-2017-03-771576. Epub 2017 Sep 29.

Abstract

T-cell differentiation is governed by interactions with thymic epithelial cells (TECs) and defects in this process undermine immune function and tolerance. To uncover new strategies to restore thymic function and adaptive immunity in immunodeficiency, we sought to determine the molecular mechanisms that control life and death decisions in TECs. Guided by gene expression profiling, we created mouse models that specifically deleted prosurvival genes in TECs. We found that although BCL-2 and BCL-XL were dispensable for TEC homeostasis, MCL-1 deficiency impacted on TECs as early as embryonic day 15.5, resulting in early thymic atrophy and T-cell lymphopenia, with near complete loss of thymic tissue by 2 months of age. MCL-1 was not necessary for TEC differentiation but was continually required for the survival of mature cortical and medullary TECs and the maintenance of thymic architecture. A screen of TEC trophic factors in organ cultures showed that epidermal growth factor upregulated MCL-1 via MAPK/ERK kinase activity, providing a molecular mechanism for the support of TEC survival. This signaling axis governing TEC survival and thymic function represents a new target for strategies for thymic protection and regeneration.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Differentiation / genetics
  • Cell Differentiation / immunology
  • Cell Survival / drug effects
  • Cell Survival / genetics*
  • Epidermal Growth Factor / pharmacology
  • Epithelial Cells / drug effects
  • Epithelial Cells / metabolism*
  • Female
  • Gene Expression
  • Gene Expression Profiling
  • Gene Expression Regulation
  • Gene Knockdown Techniques
  • Homeostasis / genetics
  • Immunophenotyping
  • Lymphopenia / genetics
  • Male
  • Mice
  • Mice, Knockout
  • Myeloid Cell Leukemia Sequence 1 Protein / genetics*
  • Myeloid Cell Leukemia Sequence 1 Protein / metabolism*
  • Proto-Oncogene Proteins c-bcl-2 / genetics
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • T-Lymphocyte Subsets / cytology
  • T-Lymphocyte Subsets / immunology
  • T-Lymphocyte Subsets / metabolism
  • Thymocytes / cytology
  • Thymocytes / immunology
  • Thymocytes / metabolism
  • Thymus Gland / pathology
  • Thymus Gland / physiology*
  • bcl-X Protein / genetics
  • bcl-X Protein / metabolism

Substances

  • Myeloid Cell Leukemia Sequence 1 Protein
  • Proto-Oncogene Proteins c-bcl-2
  • bcl-X Protein
  • Epidermal Growth Factor